Oncosupporessive gene

ABSTRACT

Isolation and characterization of an oncosuppressive gene which is involved in the apoptotic process and is regulated by p53 ad p73, polypeptide thereby encoded, sequences involved in gene regulation and genetic constructs thereof.

[0001] The present invention regards the isolation and characterization of a novel gene which is involved in programmed cell-death (apoptosis) and has oncosuppressive activity. The gene is regulated by p53 and p73, which are known to activate the transcription of genes involved in cell-cycle block and apoptosis. p73 and p53 have homologous sequences, especially in the central region including the DNA-binding domain, and share a common pattern of gene-activation. However, their oncosuppressive activities, in particular the pro-apoptotic effects, are not completely clarified. Therefore the search of genes activated by p53 and p73 attracts a great scientific and applicative interest.

PRIOR ART

[0002] Nagase et al., DNA Research 3, 321-329 (1996), reports the sequencing of human cDNA clones obtained from a library of human cDNAs, and the predicted coding sequences of 80 new genes (KIAA0201 to KIAA0280) deduced by analysis of cDNA clones. The coding sequence named KIAA0247 is present in the gene isolated according to this invention. The referenced publication does not contain information as to the structure and function of the gene.

[0003] WO01/18542 lists a huge number of cDNA sequences identified by subtraction library construction, which are overexpressed in ovarian tumor cells and hence proposed for use as ovarian cancer markers. Sequence n. 1.18 shows high homology with the coding sequence of the present gene.

DESCRIPTION OF INVENTION

[0004] In differential-display experiments with human ovarian carcinoma cells A2780, a cDNA fragment whose expression increased after treating the cells with a synthetic derivative of distamycin A was identified. This compound is known to interact with the DNA minor groove.

[0005] The same effect was observed with cytotoxic compounds differing from distamycin A by their mechanism of action, such as cisplatin, taxol, doxorubicin and fluorouracil; obtaining in each case an increased production of the same fragment.

[0006] To verify whether the increase was mediated by p53, the effects of antitumnor drugs were evaluated in isogenic model-systems differing for p53 expression. An increased transcription of the isolated cDNA could not be observed in cells where the p53 gene had been inactivated, suggesting that the activity of the gene under investigation is regulated by p53.

[0007] The complete cDNA containing the isolated fragment was then isolated from a cDNA-library and entirely sequenced. It has 5338 base pairs (SEQ ID N. 1) and codes for a protein of 303 amino acids (SEQ ID N. 2). The coding region spans nucleotides 269 to 1177 (1180, including the stop codon “tga”), while nucleotides 1180-5338, which form the non-translated 3′ region (SEQ ID N. 3), are involved in the regulation of protein synthesis by controlling the stability of the corresponding transcript.

[0008] In a first embodiment the invention is directed to a DNA molecule having sequence SEQ ID No. 1. In a further embodiment the invention provides SEQ ID N. 3, which is the sequence complementary to the non-translated mRNA region involved in the regulation of protein synthesis.

[0009] Included within the scope of the invention are also nucleic acid molecules, their stable analogs or mimetics, such as PNA (Peptide Nucleic Acid) molecules, or other derivatives thereof that do not undergo in vivo degradation or biotransformation, which can hybridize to the DNA molecule of SEQ ID No. 3, or to a complementary sequence thereof. Such products can be used to modulate the function of the regulatory sequence contained in the transcript of the isolated gene. As herein used, the term “hybridization” may refer to stringent or non-stringent conditions. These can be easily determined by anyone skilled in the art following known protocols (see for example Sambrook, “Molecular Cloning, A Laboratory Manual”, Cold Spring Harbor Laboratory, N.Y. (1989), or Ausbel, “Current Protocols In Molecular Biology”, Green Publishing Associates and Wiley Interscience, N.Y. (1989)).

[0010] The protein encoded by the complete cDNA was biochemically characterized. It showed a molecular weight, calculated by SDS-PAGE, of 30-35 kDa, consistent with the number of amino acids (303) deducible from the sequence. To determine its cellular location, fusion proteins were prepared from constructs combining the isolated c-DNA sequence with sequences coding for proteins or protein fragments detectable by microscopy, such as HA, FLAG or GFP. In these experiments the cells were transiently transfected and examined at different times. The expression product bearing the GFP protein was found to locate within cell vesicles and membranes. The same location was observed in different human and murine cell lines. Further, morphologic changes following gene overexpression were evaluated in transiently transfected cells. Several cytoplasmic vacuoles were present in cells transfected with the GFP-cDNA construct. In some cases the cell membranes appeared disrupted and the vacuole content was extra-cellularly released. The same effects were previously reported for apoptotic cell lines other than those of type II (where nuclear fragmentation occurs).

[0011] According to a further aspect, the invention is directed to the polypeptide SEQ ID N. 2 and to its DNA coding sequence SEQ ID N. 4. Included are also sequence variants of the polypeptide SEQ ID N. 2, due to substitution, addition or deletion of one or more amino acids, provided that its specific functions are maintained. As to the deletion variants, peptides generated by repeated deletions at the N-terminus of SEQ ID N. 2 showed an activity similar to that of the parent polypeptide. In particular, (poly)peptides 12-303, 23-303, 35-303, 49-303, 60-303 and 74-303 (referred to nucleotide positions in SEQ ID N. 2), which were found to maintain the same oncosoppressive activity as the parent polypeptide, represent a further object of the invention.

[0012] Using the information available with the fall-length cDNA, the structure of the human oncosuppressive gene (DRAGO) was molecularly characterized. It consists of 6 exons, the first of which (188 bp) forming the non-translated 5′ region. Exons 2,3,4 and 5 (201, 198, 140 and 427 bp respectively) correspond to the coding region which contains the first 26 bases of exon 6 (4184 bp) and additionally the entire non-translated 3′, region. Interestingly, the gene presents two large introns (45-50 kb) between exons 1-2 and 2-3, respectively. The presence of such introns, and of the large untranslated region as well, implies a strong gene regulation. Starting from a 10735 bp region located upstream of the first exon (SEQ ID N. 5), a 3761 bp fragment (SEQ ID N. 6), consisting of the first intron, the first exon and a sequence portion contiguous to exon-1 5′-end, was isolated. This fragment was functionally linked to a reporter gene (luciferase) to determine its transcription promoter activity. In p53-defective cells, a sustained transcription of the reporter gene could be detected. In cells where p53 functionality had been restored by co-transfection of a vector carrying the p53 gene under the control of a strong viral promoter, the promoter activity of the 3761 fragment was two-fold increased. This result is consistent with the experiments conducted in isogenic p53⁺ or p53⁻ model-systems. The observed p53 regulation is similar to that of other p53-responsive promoters such as the p21-gene promoter.

[0013] An even stronger promoter activity in response to p73 and p53 was observed with fragments of the 3761 bp sequence. In experiments where cells were co-transfected with DNA fragments—SEQ ID. No. 9 to 15—subcloned upstream of the luciferase gene and with either p73- or p53-encoding plasmids, a high expression of the reporter was found.

[0014] Sequences SEQ ID N. 5-6 and 9-15, which are endowed with transcription promoter activity responsive to p53 and p73, are embodiments of this invention. They can be used in the preparation of gene constructs and vectors useful for the study of oncosuppressive-gene expression. In particular these sequences, as well as the untranslated regulatory sequence of SEQ ID N. 3, can be used for the screening of compounds that modulate the expression of the oncosuppressive product. In a typical assay, the candidate compound is incubated with cells transfected with the regulatory sequences operatively linked to a suitable reporter gene, and then the ability of the e compound to modulate the expression of the reporter gene and/or to modify particular cell functions or properties, such as their growth in response to particular stimuli, is determined. Moreover, animals transgenic for the same sequences can be produced. In a further application, animal models carrying particular tumors can be used to study the ability of candidate compounds to modulate the expression of the oncosuppressive gene.

[0015] The murine oncosuppressive gene was also cloned and resulted highly homologous to the human gene, with a nucleotide (SEQ ID N. 7) and amino acid (SEQ ID N. 8) identity of 87% and 88%, respectively.

[0016] The identification of murine gene sequences enables the preparation of knock-out mice. A suitable strategy can be summarized as follows. Initially, a region of the gene of approx. 6-7 kb, preferably containing the exons 3-5, after insertion in a suitable vector, is partially replaced by a gene conferring antibiotic resistance, such as the neomycin-resistance gene, which, besides functioning as selection marker, causes inactivation of the oncosuppressive gene by interrupting its transcription.

[0017] ES cells are then transfected with the recombinant construct and only those keeping viable and growing in a medium added with the antibiotic are selected. The positive clones are then identified by PCR and Southern blot and introduced into blastocysts by microinjection. The thus generated chimera mice are initially heterozygous (−/+) and then, after breeding, homozygous (−/−) for the inactivated gene.

DESCRIPTION OF THE FIGURES

[0018]FIG. 1. Differential display analysis of gene expression in A2780 cells untreated or treated with a distamycin derivative for 1 hour. The RNA was extracted 1, 6 or 24 hours after treatment.

[0019]FIG. 2. Northern blot confirming the increased expression of fragment 1 mRNA (FIG. 1).

[0020]FIG. 3. RT-PCR analysis of the isolated-cDNA expression in control cells (C) and in cells treated with cisplatin (DDP).

[0021]FIG. 4. SDS PAGE—the protein produced in vitro from the isolated cDNA is indicated by an arrow. Gel stained with Coomassie Blue.

[0022]FIG. 5. Staining of A2780 colonies recovered after transfection with a control vector (pCDNA3) or with a vector containing the isolated cDNA.

[0023]FIG. 6. RT-PCR analysis of the isolated-cDNA expression in murine embryonic fibroblasts from wild-type mice (+/+) or p53 (−/−) knock-out mice, treated or not with the distamycin derivative for 1 hour. The RNA was extracted 1, 6 or 24 hours after treatment.

[0024]FIG. 7. RT-PCR analysis of isolated-cDNA expression in HCT116 cells expressing wild-type. p53 (+/+) or in HCT116 cells p53-inactivated by homologous recombination (−/−), treated or not (Controls) with the. distamycin-A derivative for 1 hour. The RNA was extracted 1, 6 or 24 hours after treatment.

[0025]FIG. 8. Molecular structure of the gene, indicating the number of base pairs of each exon.

[0026]FIG. 9. Transcription-promoter activity of a 3761 bp fragment containing the first intron, the first exon and the region contiguous to the 5′-end of the first exon. The fragment was subcloned upstream of the luciferase gene and co-transfected with p53-expressing or p53-defective vectors. p21 promoter was used as control for the p53-responsive control gene. Sub-cloning vector: PGL2.

[0027]FIG. 10. Transcription-promoter activity of 2.5 Kb fragment linked to luciferase gene was evaluated in p53 (−/−) Saos-2 cells in cotransfection experiments with p73 different isoforms and p53. Activation of 2.5 Kb lo fragment was compared with p21 promoter.

[0028]FIG. 11. DN-p73 repression of transcription activity of p73α and p73γ on p21-luciferase promoter. Increasing concentration of DN-p73 was used in co-transfection experiments with p73α and p73γ.

[0029]FIG. 12. DN-p73 cooperation with p73α, p73β, p73γ, p73δ in transactivation of 2.5 Kb fragment-luciferase construct with increasing concentrations of DN-p73. The first column shows induction of 2.5 Kb fragment by DN-p73 alone.

[0030]FIG. 13. Response of 3761 bp fragment and deleted mutants to p53 and p73α, p73β, p73γ, p73δ. Fragments were subcloned upstream to the 20 luciferase gene. (the sequences of fragments 2.5 KB, SmaI, PstI(a)+PstI(b), PH3, HP4, SP5 and 964 bp are respectively reported in SEQ ID N.: 9, 10, 12+13, 11, 14, 15, 16)

EXAMPLES Example 1 Isolation and Characterization of the Human cDNA

[0031] Human ovary carcinoma A2780 cells were treated for 1 hour with an antitumor derivative of distamycin-A at its 50% growth-inhibiting concentration; at the end of the treatment and after 6 and 24 hours the total RNA was isolated by column extraction (SVTotal RNA, Promega Italia) and reverse-transcribed using poly-T primers as indicated in the differential-display kit (GenHunter). The fragments thus obtained were separated on denaturing polyacrylamide gel and detected by autoradiography. The bands whose intensity differed from controls were isolated and purified. One of them (fragment 1), after purification and ³²P-labeling (rediprime kit, Amersham), was used as probe in Northern Blot experiments. The RNA from the same cells was separated on agarose gel, transferred onto nylon membrane and hybridized with the probe.

[0032] To isolate the complete cDNA containing fragment 1, a cDNA library

[0033] Human ovary carcinoma A2780 cells were treated for 1 hour with an prepared from human fibroblasts using λgt10 vector was hybridized with the probe (see “Molecular Cloning, A Laboratory Manual”, Cold Spring Harbor Laboratory, N.Y. (1989), or Ausbel, “Current Protocols In Molecular Biology”, Green Publishing Associates and Wiley Interscience, N.Y. (1989)). The positive clones were isolated, sequenced and the full-length cDNA (5338 bp) was cloned in pBluescript vector (Stratagene). The coding region results comprised between nucleotides 269 and 1177 (1180 including the stop codon “tga”) whereas the remaining 4158 nucleotides form the non-translated 3′ region.

Example 2 Analysis of cDNA Expression in Cells Treated with Different Cytotoxic Agents

[0034] PCR experiments using oligonucleotides derived from the isolated cDNA evidenced an increase of mRNA production in cells treated with different antitumor compounds other than distamycin and having a different mechanism of action with respect to the latter, such as cisplatin and taxol, which cause DNA damage and microtubule stabilization, respectively.

[0035] Cells A2780 were treated with taxol and cisplatin (DDP) and the RNA was extracted before and 24 hours after the treatment. The amount of specific mRNA was determined by PCR following reverse-transcription of the total RNA (1 μg) with primers derived from the coding region of fragment 1 (5′-ctcgagtgccatggcaggatagcacc and 5′-tctagatcatgcttctttcaacagtg), according to the protocol supplied in the RNA-PCR kit (Perkin Elmer). The amplified fragment (923 bp) was separated on agarose gel. A fragment of beta-actin gene was used as internal control. FIG. 3 shows the results obtained treating the cells with cisplatin (DDP): the band associated with the isolated gene is more intense than that of control cells (C) in conditions in which the levels of beta-actin gene are comparable in the two groups. Similar results were obtained using taxol and other antitumor drugs.

Example 3 Protein Characterization and Intracellular Location

[0036] Using the isolated full-length cDNA as template, a polypeptide was produced (Promega TNT express kit) with an apparent molecular weight, calculated by SDS-PAGE, of 30-35 kDa (FIG. 4). This mol weight is consistent with the structure of the polypeptide and with the number of amino acids (303) deducible from its sequence (SEQ ID N. 2).

[0037] Transient transfection experiments were conducted to determine the intracellular location of the polypeptide. To this end, the latter was fused to proteins or protein fragments such as HA or FLAG, which can be detected by microscopy using fluorescent antibodies, or GFP, which is an intrinsically fluorescent protein. In these experiments the cells were analyzed 24 and 48 hrs after transfection with different constructs. Using a GFP-construct, the polypeptide was found to localize within cellular vesicles and membranous structures. Under the same conditions, as expected, GFP alone was uniformly located within the cell. The same effects were observed in different human and murine cell lines.

[0038] Transient transfection experiments were also conducted to assess morphologic modifications occurring 24 and 48 hrs after gene overexpression. Cells transiently transfected with a GFP construct showed in all cases the presence of several cytoplasmic vacuoles, less frequently the membrane appeared disrupted and the vacuole content released in the extracellular areas. Transfection with GFP alone was not associated with any evident morphologic alteration.

Example 4 Effects of Gene Overexpression in Eukaryotic Cells

[0039] The effects of gene overexpression were evaluated in cells carrying constructs in which the isolated cDNA was functionally linked to a strong viral promoter.

[0040] The complete cDNA (5338 bp) and the coding region (nucleotides 1-1180) were used for vector assembly. The two sequences were excised from pBS plasmid (Stratagene) and inserted into pCDNA3 (Invitrogen), pCDNA3-HA and pCDNA3-FLAG expression vectors. These two latter were prepared from pCDNA3 by insertion of the HA and FLAG coding sequences. The coding portion of the isolated cDNA was amplified by PCR (primers: 5′-ctcgagtgcatggcaggatagcacc and 5′-tctagatcatgcttctttcaacagtg) and sub-cloned in frame with the HA and FLAG sequences. Similar constructs were prepared from GFP (green fluorescent protein). In this case, the coding sequence of the isolated cDNA was subcloned in frame with the GFP cDNA in a pEGFP-C1 vector (Clontech). Each construct was automatically sequenced to verify its correct assembly and transfected into A2780 cells by calcium phosphate precipitation, according to the following procedure. 5-10 micrograms of plasmidic DNA were mixed with calcium chloride and phosphate buffer to form fine calcium phosphate precipitates, and this mixture was applied to a cell culture (70% confluence) for a period of 12-16 hrs. The cells were rinsed 25 with PBS, rested for 48 hrs, counted and plated (5000 cells/10 cm plate) in a culture medium added with neomycin. 15 days later the culture medium was removed and the colonies dyed with crystal violet, washed and photographed. FIG. 5 shows the photograph of a plate in which A2780 cells were transfected with the isolated cDNA or with vector pCDNA3 alone. No colonies could be detected in cDNA-bearing cells, whereas several colonies were present in the culture treated with vector alone. The overexpression of the complete cDNA (5338 bp) or its 1180 bp fragment (coding region) prevented colony formation. This effect was observed in A2780 cells (ovary carcinoma), SaoS2 and U2OS lines (human osteosarcoma), and 3T3 lines (murine fibroblasts). Failure to isolate stable clones was due to the strong growth-suppressing effect following gene-overexpression.

Example 5 Role of p53 in Gene Activation

[0041] To ascertain whether the activity of the gene was mediated by p53, the effects of antitumor drugs in isogenic models with different p53 expression were examined. No expression was found in embryonic fibroblasts from p53 knock-out mice (FIG. 6). In these experiments, fibroblasts from wild-type and p53 knock-out mice were treated with a distamycin derivative for 1 hour. The RNA isolated 1, 6 and 24 hours after the treatment was used to amplify a cDNA containing the coding portion of the murine gene (primers: 5′-ctcgagtgccatggcaggatagcacc and 5′ -tctagatcatgcttctttcaacagtg). The antitumor compound failed to induce gene expression in a HCT116 clone where p53 had been inactivated by homologous recombination (HCT116 p53 −/−); in contrast, gene expression was observed in the parental cell line (FIG. 7). The same conditions as in the experiments with embryonic fibroblasts were used. These results demonstrate that p53 is necessary for gene activation.

Example 6 Molecular Characterization of the Human Gene

[0042] A pCYPAC2-subcloned PAC RPCI1 genomic library from the UK Human Genome Mapping Project Resource Center was used (Hinxton, UK). This library was established from the blood of a healthy subject and consisted of approx. 120000 clones spotted in duplicate on 7 membrane filters (22.2×22.2 cm). A 5′-fragment (160 bp) generated by PCR (primers: 5′-ctcgagtgccatggcaggatagcacc and 5 ′-tctagatcatgcttctttcaacagtg) was used as hybridization probe. The latter was ³²P-labeled and incubated with the filters for 16 hrs. After extensive washing, the filters were exposed to an autoradiographic film. Two positive clones (92D20 and 67A24) were identified and the genomic DNA of one of them was partially sequenced (terminal regions). Using sequence information available from a database, the structure of the gene was defined.

Example 7 Role of p53 in Gene Transcription

[0043] The region (10735 bp—SEQ ID N. 5) located upstream of the first exon was isolated from one PAC clone. A portion of it (3761 bp), containing the first intron (partially), the first exon and a region adjacent to the 5′-end of exon 1, was sub-cloned in pGL2 vector (Promega) upstream of the luciferase gene. A significant transcription of the reporter gene was detected with a luninometer 48 hrs after transfection of semi-confluent p53⁻ cells with the construct (10 μg). Cells transfected with pGL2 vector alone (without the 3761 bp fragment) were used as the control.

[0044] In co-transfection experiments, the cells were transfected with both the same construct and an expression vector containing the entire p53 gene under the control of a strong viral promoter. In the presence of p53, the isolated fragment (3761 bp) induced a transcription of the reporter gene two fold higher than in its absence, which is consistent with the results of the experiments carried out in isogenic models differing for p53 expression (FIG. 9).

Example 8 Role of p73 in Gene Transcription

[0045] Different isoforms of p73 are generated by alternative splicing of p73 gene. The full length protein is defined as alpha p73 and at least 4 isoforms (beta, gamma, delta and epsilon) have been described so far. These isoforms can have different transcriptional activation potency. An additional, truncated form of p73 lacking the first 3 exons has been described. This form, named DNp73, does not result from a different splicing, but utilizes an additional promoter, positioned between exons 3 and 4 of the wt protein. The DNp73 protein has been shown to bind DNA but is not able to activate transcription for lack of the transactivation domain.

[0046] Experiments were carried out in which the 3761 bp fragment (SEQ ID n. 6) was subcloned in the pGL2 vector upstream of the luciferase gene and used to determine p73-dependent gene transcription. A further deletion of SEQ ID N. 6 generated a fragment of 2.5 Kb (SEQ ID N. 9) that was used to test the specific activity of different p73 isoforms.

[0047] Cells were co-transfected with the pGL2-derived construct and with expression plasmids containing the full-length regions coding for p53 and for different p73 isoforms. 48 hours after transfection, cells were lysed and the luciferase activity measured by standard, commercially available kits (Promega).

[0048] A typical experiment is reported in FIG. (10), showing the ability of p53 and of different p73 isoforms to activate the promoter region (single experiment).

[0049] p73 is a stronger activator of the promoter fragment than p53. Among different p73 isoforms, beta and gamma isoforms are the strongest.

[0050] To test the ability of DN-p73 to block p73-induced transactivation, we have conducted experiments in which the promoter-luciferase construct has been cotransfected with the expression plasmid. As a control we have used the p21-luciferase construct. As expected, increasing the amount of DNp73, transactivation of p21 promoter by p73 tends to decrease (FIG. 11). With 2.5 Kb fragment-pGL2 construct, increasing amounts of DNp73 determined a concentration-dependent increase of luciferase activity, which suggests a cooperation between p73 and DNp73 in transactivating this DNA sequence. DNp73 is also able to transactivate 2.5 Kb fragment-luciferase construct when transfected in the absence of p53 or p73. This effect is not observed with the p21 promoter sequence (FIG. 12)

Example 9 Fragments Retaining Promoter Activity

[0051] Fragments of the 3761 bp DNA were generated (FIG. 13). These fragments, subcloned upstream to the luciferase gene, have been co-transfected with p73 and p53 expressing plasmids in an attempt to restrict the DNA region responsible for the p53- and p73-dependent transactivation.

[0052] In FIG. 13 the luciferase activities are reported. The sequence of 2.5Kb results particularly responsive to p73.

[0053] The fragment of 964 bp (SEQ ID N. 16) does not respond to any of the p73 isoforms nor to p53. Further deletions of the 3761 bp sequence retain a promoter activity responsive to p73, particularly to the beta and gamma isoforms, while the p53-dependent luciferase activity was almost abolished. The SP5 fragment (577 base pairs) is particularly responsive to p73 gamma.

Example 10 Isolation of Murine cDNA

[0054] In consideration of the high oncosuppressive effect exerted by the isolated gene, its murine homologue was cloned via PCR using primers derived from the human sequence. The identity was 87% for the nucleotide sequence and 88% for the amino acid sequence (SEQ ID N. 7-8, respectively).

[0055] The RNA from 3T3 murine fibroblasts was reverse-transcribed (random hexamers—RNA PCR kit Perkin Elmer) and used for the amplification of a 909 bp fragment (primers 5′-ctcgagtgccatggcaggatagcacc and 5′-tctagatcatgcttctttcaacagtg)

[0056] The isolated fragment (nt 1-906; the terminal “tga” is a stop codon) codes for a 302 aa polypeptide (i.e. 1 aa less than the corresponding human polypeptide).

1 19 1 5338 DNA Homo sapiens 1 ccgaagccgg cgaccgcccc acctcctccc tccctcccgc ccgcttcctc tgcccacagc 60 gccggccaga gcgagctaga caagggcacg cggggcctcg cctagacccg agaagactgc 120 gggcgcgcgc aagcggcggc gtggaagctg tgagcgcccc catcccggag gtctccgccg 180 gctcccgggt gaatcagctc ccggccgact ttaggattct tctggatttt aaattttttc 240 tttttaaaaa aacttggacg gataaaagat gtgccatggc aggatagcac caaagagcac 300 ctcagtgttt gccgtggcct ccgtgggaca tggagtgttc cttccgctag tgatcctttg 360 caccctgctt ggagacggac ttgcttccgt gtgcccccta ccaccggagc cagagaatgg 420 tggctacatc tgccaccccc ggccctgcag agaccccctg acagcaggca gtgtcatcga 480 atacctgtgt gctgaaggct acatgttgaa gggcgattac aaatacctga cgtgtaagaa 540 tggcgagtgg aaaccagcca tggagattag ctgccgtctc aacgaggata aagacaccca 600 cacatcactt ggggtcccca cgctgtctat agtggcttct actgccagct ccgtggcgct 660 cattctcctc ctcgtggtgc tgtttgtgct gctgcagcca aagctgaagt ctttccatca 720 tagcaggcgt gaccaggggg tatctgggga ccaggtctcc atcatggtgg atggagtcca 780 ggttgcacta ccatcatacg aggaggctgt atatggcagt tctggtcact gtgtgccacc 840 tgctgacccc agagtacaga ttgtgctgtc agaagggtct gggcccagtg ggaggagcgt 900 gccaagggag caacagctgc cggaccaagg ggcctgctcc tctgcaggtg gagaagatga 960 ggccccaggc cagtctggac tatgtgaagc ctggggctct cgggcctcag agactgtgat 1020 ggtgcatcag gcaaccacct cttcctgggt ggccggctca gggaaccgcc aactggcaca 1080 caaagaaact gcagattcag agaacagtga catacaaagc cttttatccc tcacgtcaga 1140 ggagtacaca gatgatattc cactgttgaa agaagcatga gggcagcggc cagcctttcc 1200 tctctgcgag gttctctcag cccttcctcc ctctccctgt gggattgagc accctgtact 1260 ctccagccac cttacctgga tacctgagct gccacctgtg tatctgtgta tctctgaggg 1320 ccctataggc ccaccttgct ggaaactcaa ggaagattct cgccatctgc ctgttggaca 1380 gctggaggag ctggctcttt gcctggcccc gccttcccat ctgtcagaga catatttgaa 1440 tgtgctggat caaaccctcc cttttcctaa gcctctgggt cccctccagc cagctctttg 1500 gcggcagccc ccaccagctc ctgtgggcct gagtgctgct gtgtttactt gtgcctttcc 1560 cccaccctgt ccagtttccc tgtcatgcag acttgttgct gtccacaagc cttagtggct 1620 gcactgctgc cccctgccac acagggggcc gggcctgggt ctgtcctgtt tcctttgagg 1680 gttgccccta ctgccctttg caggaacaga tccaggtgtg agagctcttg agtcaagagt 1740 ggcagaagtg gctctaattg gggtgagagt gtagtccctg ggcttgccct gggttgaccc 1800 tggtggcata tttccttggc cgaggatgga agatttggag aatcatgtcc atgctggccc 1860 aggacccagc catctggccc aaaggcacaa gctcctggcc ctgttgagtt gagagtttcc 1920 aagaagcatc cagaagatcc caagggagag aaggaaaatg gctgataatg attgtcttcc 1980 taatatgcaa gttctcactt cctacttcca gcatcggcct tcctggcctt gtcttttttt 2040 tgtttccctg gagtataatg ggaagttgca tgctgcctcc tgggttttat cccagatagc 2100 tctggctttc ttgctgccca caggggcctg gggcaggaag gagacttgct gagatgccat 2160 ggagtgccca tctggtcact ggcagtctgg gcaggttgcc cctttctggg tttgtggtga 2220 cggaggggag gccgagaggc acagaccaag tccccgggtg gctgcaggca gctccagccc 2280 ggtcctgagg atcctcctca ccatggtcac gtgccttagt aactgtgccc aggaagtggc 2340 ctgctgcttg ctgtgctgct gcttttccta cttctgccct tccctgccac ccctcgcatg 2400 tcacagctga caagcaattc cttgtcttcc ctggccccct gggggaaggg ctgagaaaca 2460 gtccatgtgc accccaacct taatggcctg aggtgggcag aggggtgtgg agcagcctgg 2520 agtacagggc cctgggggag gagcccactg atgaggggcg ctctcccata gccatgtgtt 2580 gaatgctaac taggctgggg tggacgaact ctgccaactg ctgtcatctt agaagataga 2640 tgcagcagta aggaatgttt gttttgcttt tttctgaaat tttctgaagc actgtggctg 2700 ggaaacttcg aagcggaccc tgtgctgcat gtctgctcct cccctgagcc tgtctgcttg 2760 ggggtggtaa aaataaaaat cccagtttat tttcagtacc ttacctaaca gggttggctc 2820 caggcgtggg tggcctagaa gatgagggga gtggtcttct cccagccttt taccctcttg 2880 cctcctgcct ccgcgcttac acacgcactt taccacccgg tcattccctg gcctcttgct 2940 gccacttgta gtcttccttc cttcctctca gggtaagggc agtgcctgct gtgcctgttg 3000 gccactccca cacttcccct cccccaggag ccctcatctg ctgtgctgag tccaggaaag 3060 catagttagg tagggagctg gttggagaag gtgctagaac tagaaggcag atgagactag 3120 catgggccca cctggagggc tgtccctaat ggccccagtc gccttacctc acccacagca 3180 gtgcccttgt cttcctccaa aacagaaagc agtgacaaaa gggggagggg tggtaatctg 3240 aagtctcact gctgagcctt cagcttttat ttttcactgt ttcaaaaccc gcattctatt 3300 ctagaatggt ttttaaaatg gaagatctta cctttttcta tcttgttact ctggggtttt 3360 gtccccctaa gagattgcac tttttgtttg gggtttattc agctgcatag atgaccagct 3420 tgatccctgg tgaaatgaaa agccttcctt ctcctgaagc ctctttccgc cctgccctcc 3480 actaacaaca ctgaggagca caagcccagg cttgcccacc tggtaggaaa ggaagaaatt 3540 agaacaatgg gagccttggc tcccctctcg tctcctcccc tccttcttgt cactggcttt 3600 gatgaggccc acttcccaga ggctcctggg cctgtgagtg caggagctca ttctcccctc 3660 actgctgaag tctgtgacag cttcttcctc cagttatgtc tttcttccaa agcaatttct 3720 taaccatcag ccatgtgctg ctatttctag ggcttctggg ctttgtccct tactgagaga 3780 ttagggactc cacagctgcc ttgaggtagg gcctggctga gagacaaggg tagcagcagg 3840 tggcaggctg ttaaaagaca ggctgcctga ggagcctgga gcaggtggaa acaggtggaa 3900 gaaaccggcc acagccctgc tttaccgggc tcacctctag ggcattccag caagaggctg 3960 atgcaggaga atggccagca ccaaaggaca tttaaaagag tttttgggtt tttttgtttg 4020 tttgttgttg gtgtttgttt tttttttttt ttttttggca cacttgagct gactcagtgc 4080 aggtttaata tcctggtgac ttgcagtcac attctaatga ctttcaaggg ccagaatatg 4140 gtgaaaatca cttaaaatat ccgtcccttc catgccttag tttagcaggt aggctctatc 4200 ttttgccatt tctgtatttt atgtgctgtg ttcccgtttc actgggtatg aactgtgaaa 4260 tggactgaat cctggccact ttatgagttt gtttggtttt ataaggcatt tcaatgtaca 4320 ttctataaat acaagcactc catttgcaaa cagatcttaa gctaatattt tctttcccat 4380 tcatcttgcc ctccccctcc tcccaccagc tttaaagttc agtggagaag ccagatggca 4440 attcagacaa aggtatactc ttcctgcttc atgggtggtg gcacgggaat agatagccct 4500 tagccctttc cctcccagtc ccagctgagc cctcagacca cttgcttccc acataacaat 4560 gtcgcctcca tttccgagga acatccttgc gtagagaatg aaatatgctg caatcatttc 4620 tgcatcctta ctcctcaccc ccaaagaaaa aaaaaaggcc tagcagggaa gcagcatgca 4680 ggcttcacag cttaatgcca aggacagcga gtgaggctgg gagcttctct tgggcctgct 4740 gggtctgtca gctctcggaa tagggacagt ccttactggt gccccaaggt gggacttgga 4800 gaatattttg cttggcatat gtttggtctg aatggtgtag ttgctggttc cctagagagg 4860 aaaaggtggc aggcccagct ttgctgggaa atggctctta atttccagtt gaaaccctag 4920 tagaattgtg aatgaaaacc tcaaggttga gcccctctgc caagcagcag agctagtaga 4980 aggggatgca ggggcaaagc actcagttgc caagcaagga ggagagatgt acgtgggctg 5040 tgtggcagtc cccacaccct gccctggctt cttcaggtta tcgcaccact atggaatcct 5100 ttgcagaatg gtactcatat aatggtttaa aacaacacat tcataattga ctctgtgcag 5160 gatgtcactc aatcagtttg ggtttgcttt attttatttt atatatatat tttttggtat 5220 cctgtacatt gcagtgggtg tgaagatagt attttaatat ttgtacaaag tttaatttaa 5280 ttttaattgt tctatgtata taactgcatt tctaaataat taaaaaaaag ttcttatg 5338 2 303 PRT Homo sapiens 2 Met Cys His Gly Arg Ile Ala Pro Lys Ser Thr Ser Val Phe Ala Val 1 5 10 15 Ala Ser Val Gly His Gly Val Phe Leu Pro Leu Val Ile Leu Cys Thr 20 25 30 Leu Leu Gly Asp Gly Leu Ala Ser Val Cys Pro Leu Pro Pro Glu Pro 35 40 45 Glu Asn Gly Gly Tyr Ile Cys His Pro Arg Pro Cys Arg Asp Pro Leu 50 55 60 Thr Ala Gly Ser Val Ile Glu Tyr Leu Cys Ala Glu Gly Tyr Met Leu 65 70 75 80 Lys Gly Asp Tyr Lys Tyr Leu Thr Cys Lys Asn Gly Glu Trp Lys Pro 85 90 95 Ala Met Glu Ile Ser Cys Arg Leu Asn Glu Asp Lys Asp Thr His Thr 100 105 110 Ser Leu Gly Val Pro Thr Leu Ser Ile Val Ala Ser Thr Ala Ser Ser 115 120 125 Val Ala Leu Ile Leu Leu Leu Val Val Leu Phe Val Leu Leu Gln Pro 130 135 140 Lys Leu Lys Ser Phe His His Ser Arg Arg Asp Gln Gly Val Ser Gly 145 150 155 160 Asp Gln Val Ser Ile Met Val Asp Gly Val Gln Val Ala Leu Pro Ser 165 170 175 Tyr Glu Glu Ala Val Tyr Gly Ser Ser Gly His Cys Val Pro Pro Ala 180 185 190 Asp Pro Arg Val Gln Ile Val Leu Ser Glu Gly Ser Gly Pro Ser Gly 195 200 205 Arg Ser Val Pro Arg Glu Gln Gln Leu Pro Asp Gln Gly Ala Cys Ser 210 215 220 Ser Ala Gly Gly Glu Asp Glu Ala Pro Gly Gln Ser Gly Leu Cys Glu 225 230 235 240 Ala Trp Gly Ser Arg Ala Ser Glu Thr Val Met Val His Gln Ala Thr 245 250 255 Thr Ser Ser Trp Val Ala Gly Ser Gly Asn Arg Gln Leu Ala His Lys 260 265 270 Glu Thr Ala Asp Ser Glu Asn Ser Asp Ile Gln Ser Leu Leu Ser Leu 275 280 285 Thr Ser Glu Glu Tyr Thr Asp Asp Ile Pro Leu Leu Lys Glu Ala 290 295 300 3 4158 DNA Homo sapiens 3 gggcagcggc cagcctttcc tctctgcgag gttctctcag cccttcctcc ctctccctgt 60 gggattgagc accctgtact ctccagccac cttacctgga tacctgagct gccacctgtg 120 tatctgtgta tctctgaggg ccctataggc ccaccttgct ggaaactcaa ggaagattct 180 cgccatctgc ctgttggaca gctggaggag ctggctcttt gcctggcccc gccttcccat 240 ctgtcagaga catatttgaa tgtgctggat caaaccctcc cttttcctaa gcctctgggt 300 cccctccagc cagctctttg gcggcagccc ccaccagctc ctgtgggcct gagtgctgct 360 gtgtttactt gtgcctttcc cccaccctgt ccagtttccc tgtcatgcag acttgttgct 420 gtccacaagc cttagtggct gcactgctgc cccctgccac acagggggcc gggcctgggt 480 ctgtcctgtt tcctttgagg gttgccccta ctgccctttg caggaacaga tccaggtgtg 540 agagctcttg agtcaagagt ggcagaagtg gctctaattg gggtgagagt gtagtccctg 600 ggcttgccct gggttgaccc tggtggcata tttccttggc cgaggatgga agatttggag 660 aatcatgtcc atgctggccc aggacccagc catctggccc aaaggcacaa gctcctggcc 720 ctgttgagtt gagagtttcc aagaagcatc cagaagatcc caagggagag aaggaaaatg 780 gctgataatg attgtcttcc taatatgcaa gttctcactt cctacttcca gcatcggcct 840 tcctggcctt gtcttttttt tgtttccctg gagtataatg ggaagttgca tgctgcctcc 900 tgggttttat cccagatagc tctggctttc ttgctgccca caggggcctg gggcaggaag 960 gagacttgct gagatgccat ggagtgccca tctggtcact ggcagtctgg gcaggttgcc 1020 cctttctggg tttgtggtga cggaggggag gccgagaggc acagaccaag tccccgggtg 1080 gctgcaggca gctccagccc ggtcctgagg atcctcctca ccatggtcac gtgccttagt 1140 aactgtgccc aggaagtggc ctgctgcttg ctgtgctgct gcttttccta cttctgccct 1200 tccctgccac ccctcgcatg tcacagctga caagcaattc cttgtcttcc ctggccccct 1260 gggggaaggg ctgagaaaca gtccatgtgc accccaacct taatggcctg aggtgggcag 1320 aggggtgtgg agcagcctgg agtacagggc cctgggggag gagcccactg atgaggggcg 1380 ctctcccata gccatgtgtt gaatgctaac taggctgggg tggacgaact ctgccaactg 1440 ctgtcatctt agaagataga tgcagcagta aggaatgttt gttttgcttt tttctgaaat 1500 tttctgaagc actgtggctg ggaaacttcg aagcggaccc tgtgctgcat gtctgctcct 1560 cccctgagcc tgtctgcttg ggggtggtaa aaataaaaat cccagtttat tttcagtacc 1620 ttacctaaca gggttggctc caggcgtggg tggcctagaa gatgagggga gtggtcttct 1680 cccagccttt taccctcttg cctcctgcct ccgcgcttac acacgcactt taccacccgg 1740 tcattccctg gcctcttgct gccacttgta gtcttccttc cttcctctca gggtaagggc 1800 agtgcctgct gtgcctgttg gccactccca cacttcccct cccccaggag ccctcatctg 1860 ctgtgctgag tccaggaaag catagttagg tagggagctg gttggagaag gtgctagaac 1920 tagaaggcag atgagactag catgggccca cctggagggc tgtccctaat ggccccagtc 1980 gccttacctc acccacagca gtgcccttgt cttcctccaa aacagaaagc agtgacaaaa 2040 gggggagggg tggtaatctg aagtctcact gctgagcctt cagcttttat ttttcactgt 2100 ttcaaaaccc gcattctatt ctagaatggt ttttaaaatg gaagatctta cctttttcta 2160 tcttgttact ctggggtttt gtccccctaa gagattgcac tttttgtttg gggtttattc 2220 agctgcatag atgaccagct tgatccctgg tgaaatgaaa agccttcctt ctcctgaagc 2280 ctctttccgc cctgccctcc actaacaaca ctgaggagca caagcccagg cttgcccacc 2340 tggtaggaaa ggaagaaatt agaacaatgg gagccttggc tcccctctcg tctcctcccc 2400 tccttcttgt cactggcttt gatgaggccc acttcccaga ggctcctggg cctgtgagtg 2460 caggagctca ttctcccctc actgctgaag tctgtgacag cttcttcctc cagttatgtc 2520 tttcttccaa agcaatttct taaccatcag ccatgtgctg ctatttctag ggcttctggg 2580 ctttgtccct tactgagaga ttagggactc cacagctgcc ttgaggtagg gcctggctga 2640 gagacaaggg tagcagcagg tggcaggctg ttaaaagaca ggctgcctga ggagcctgga 2700 gcaggtggaa acaggtggaa gaaaccggcc acagccctgc tttaccgggc tcacctctag 2760 ggcattccag caagaggctg atgcaggaga atggccagca ccaaaggaca tttaaaagag 2820 tttttgggtt tttttgtttg tttgttgttg gtgtttgttt tttttttttt ttttttggca 2880 cacttgagct gactcagtgc aggtttaata tcctggtgac ttgcagtcac attctaatga 2940 ctttcaaggg ccagaatatg gtgaaaatca cttaaaatat ccgtcccttc catgccttag 3000 tttagcaggt aggctctatc ttttgccatt tctgtatttt atgtgctgtg ttcccgtttc 3060 actgggtatg aactgtgaaa tggactgaat cctggccact ttatgagttt gtttggtttt 3120 ataaggcatt tcaatgtaca ttctataaat acaagcactc catttgcaaa cagatcttaa 3180 gctaatattt tctttcccat tcatcttgcc ctccccctcc tcccaccagc tttaaagttc 3240 agtggagaag ccagatggca attcagacaa aggtatactc ttcctgcttc atgggtggtg 3300 gcacgggaat agatagccct tagccctttc cctcccagtc ccagctgagc cctcagacca 3360 cttgcttccc acataacaat gtcgcctcca tttccgagga acatccttgc gtagagaatg 3420 aaatatgctg caatcatttc tgcatcctta ctcctcaccc ccaaagaaaa aaaaaaggcc 3480 tagcagggaa gcagcatgca ggcttcacag cttaatgcca aggacagcga gtgaggctgg 3540 gagcttctct tgggcctgct gggtctgtca gctctcggaa tagggacagt ccttactggt 3600 gccccaaggt gggacttgga gaatattttg cttggcatat gtttggtctg aatggtgtag 3660 ttgctggttc cctagagagg aaaaggtggc aggcccagct ttgctgggaa atggctctta 3720 atttccagtt gaaaccctag tagaattgtg aatgaaaacc tcaaggttga gcccctctgc 3780 caagcagcag agctagtaga aggggatgca ggggcaaagc actcagttgc caagcaagga 3840 ggagagatgt acgtgggctg tgtggcagtc cccacaccct gccctggctt cttcaggtta 3900 tcgcaccact atggaatcct ttgcagaatg gtactcatat aatggtttaa aacaacacat 3960 tcataattga ctctgtgcag gatgtcactc aatcagtttg ggtttgcttt attttatttt 4020 atatatatat tttttggtat cctgtacatt gcagtgggtg tgaagatagt attttaatat 4080 ttgtacaaag tttaatttaa ttttaattgt tctatgtata taactgcatt tctaaataat 4140 taaaaaaaag ttcttatg 4158 4 912 DNA Homo sapiens 4 atgtgccatg gcaggatagc accaaagagc acctcagtgt ttgccgtggc ctccgtggga 60 catggagtgt tccttccgct agtgatcctt tgcaccctgc ttggagacgg acttgcttcc 120 gtgtgccccc taccaccgga gccagagaat ggtggctaca tctgccaccc ccggccctgc 180 agagaccccc tgacagcagg cagtgtcatc gaatacctgt gtgctgaagg ctacatgttg 240 aagggcgatt acaaatacct gacgtgtaag aatggcgagt ggaaaccagc catggagatt 300 agctgccgtc tcaacgagga taaagacacc cacacatcac ttggggtccc cacgctgtct 360 atagtggctt ctactgccag ctccgtggcg ctcattctcc tcctcgtggt gctgtttgtg 420 ctgctgcagc caaagctgaa gtctttccat catagcaggc gtgaccaggg ggtatctggg 480 gaccaggtct ccatcatggt ggatggagtc caggttgcac taccatcata cgaggaggct 540 gtatatggca gttctggtca ctgtgtgcca cctgctgacc ccagagtaca gattgtgctg 600 tcagaagggt ctgggcccag tgggaggagc gtgccaaggg agcaacagct gccggaccaa 660 ggggcctgct cctctgcagg tggagaagat gaggccccag gccagtctgg actatgtgaa 720 gcctggggct ctcgggcctc agagactgtg atggtgcatc aggcaaccac ctcttcctgg 780 gtggccggct cagggaaccg ccaactggca cacaaagaaa ctgcagattc agagaacagt 840 gacatacaaa gccttttatc cctcacgtca gaggagtaca cagatgatat tccactgttg 900 aaagaagcat ga 912 5 10735 DNA Homo sapiens 5 ctttcagttt tccagatgta aattttcaca tttcaattgt aaatgtttag caacttgttc 60 tataggtggg agctgattta tatttagtaa tttctgtggt gtaaatactt ccactgtatc 120 tgatttcaaa ctatcaatgt gatgtcactg aatgtggagt tgagaagaga tgagaagtgg 180 cataatatga tgtagtactt cataagagat gtaaataaac ttgaaagcat agataagagt 240 ataatgtaag agaagggagg cagaaaaagt aaaaaaatac aatgtagtaa aataattaat 300 aattaggaag tggtaacttg agtatttatt actttaacaa ctataattta attttacata 360 tatataattt aattttttta atttttaatt tttttggttt tttttgagac agagtcttgc 420 tctgtcacct aagctggagt gtagtggcac aatcacagct tactttagtc ctgacctccc 480 gagctcaaat aatcctccca cctcagcctc ctgagtagct gggaccacag gcgtgtgcca 540 ccatgcctgg ctaatttttg tattttttgt aaagaggtct cactctgttg cccaggctgg 600 tctcaaactt ctgagctcaa gtgatcctcc tgctttggcc tcccaaagtg ctgggattac 660 aggcgtgagc cactgctact ggccataatt taatttttaa caaaggctgt gtttaacaac 720 tagcttacaa aaatcttgaa cattttagaa ttgattcttg acagtttgag cactcttcag 780 cacaccactg caggtaacct gctctggtcc ccctttaaaa atcacatttg gtttttacag 840 tgcaaattac agctgtattc cctaagaagc aggacatgct actagtaact gtggccttgg 900 cctcatcttt aaactttatg tacctcagtt tcctcatatg caaaatgaag ataatagtat 960 taatacctat ttcagaggct attgcaagga ttaaataaaa tcatgtatgt ggagccacta 1020 gcaaagtatc tggcagacag tacatattta atgtattgga gcttttttca ggggattcat 1080 tgacatgcct gggggcaaag ctgcaccttg gggtccatca tcagcacctt caaaataccc 1140 tgattttgga ggtatcaaaa taccctgatt ttgaaggtcc ctggccagcc aaaagaggga 1200 ctgaccctac tgatccagcc aacaagtcct ggagccaaga accttctgag gtgttgtgtc 1260 tgccagagct tcacagccct atccctgcct ccccagacag tctgaaggag ggagcaactc 1320 cattcctcta tgcactggca gctcagagct agcaaggcca atcatatagc tctgtcttct 1380 caccattaaa tcacatgaaa atgaaccatc agggagggaa tacagtgtcc aatgaccagg 1440 agctgtgtgt gtgtgtaggt gtgtgtgtgt gtatatgtgt gtgtgtgtgt gtgtgtgtgt 1500 gtatgtggga ggggtttgtg ggctggctct gtctagaaag gcctcaggcc ctaggctatc 1560 cccagtccct tccttcctcc ctgcagattg tctcctagag tcactgccca gcccttgggc 1620 aaagggcaag cagcaggtca tcaggctggt tggcaccagg ggtggggggg atctgatatt 1680 cattcatctt ccactgggat accatctgga gacatagcag gtggatgctc cctttctacc 1740 ttggcttttc cttgtgtgaa aaatggggcc aacactttta ccagttaacc tgacctgtat 1800 tagggaaaga atgttgtcaa agacatgctt cagaaaagca ggtggggctg ggttgccctc 1860 ttatatgtat ctgctaattg ggcagcctca agtgcacatt ttctaaggct agggtcagag 1920 ttggggtgga tagggaatca tagctgctgc tgtgaatagc ccagatctaa gccctgaact 1980 ctgacctcta caaagctccc tccgaccagt ggcctgcagg gattgcgtca ccaagcctgg 2040 ctctcacagg ctcctgacaa gctgcaagaa gggttgcccc tggtgatggt gcaggctcac 2100 aaattcagat aacctcctga gcctagatct tcctcctctg gagtgggagt tgcttctcag 2160 ctcctgttgg cctagccctg tacagcccac ccattttgga ctctgacatt ctgcggtgag 2220 ggtggcctca ccttccacct cctctggggt caaatgggtt taccttcaca gggctttgaa 2280 agctgcccaa ggaatcttga atcaaaacat gaaactcatg ctaatttcta tatgagatca 2340 gacaagctag caacctttca gtgcctcaac ttccttatag gtaaaattgg ggacaataat 2400 gtctcttcgt tttatgggga tgttgtaaaa aactagctgg tatgcaaaaa agcacttttt 2460 taaaaagcaa gagatatatg aggacaattt caatctttat ttgctatttt tattaggggt 2520 gggaggaagc acatggttta tttgggaaag tgtgaccttt ggaacagaca aacaagaatg 2580 aattctgctt ttgcaacata catacttatg tggttttgat atgtcaaaaa aaaaaatctc 2640 tctaagcctt gcttgtaaaa tggtgttaat gataattaac ttggaggact gttgccaaaa 2700 ttagaggtta cacgtatcaa gtccctacca agcacctgac atacagtagg tgctttgtaa 2760 atagtagctg tcattactac tattgtatgt aataaccata gcaactgaga ttccatgtac 2820 ttattctgaa ccttttctct cactttcaga gagccaaact cctctgtcct gccctgcaag 2880 cagtaaaggc acacactcct tgttatattc ctgggagatg aaaggaatac tgtgcctcct 2940 gactcttatc ataggagtga ctacctcatc ctgattggcc caggactgtc ctaattttgg 3000 cactggaagt cccatgtgcc aggaatcccc ttagtcccag gcaaactggg atggctggct 3060 attctactca ccaccaactg ggactaatct aacccccatg ccatattcca gcacctagat 3120 ttagagcaga atattaagat ttgtgctgga aattggccag gtgtggtgac tcacgcctgt 3180 aatcctagca ctttgggagg cagaagcagg ctgatcactg aggtcaggag tttgagacca 3240 gcctggctaa cgtggtgaaa ccctgtctct actaaaaata caaaaattag ctgggtgtgg 3300 gggtacgcac ctatagtccc agctactcgg gagactgaga caggagaatc ccctgaacct 3360 gggaggcgga ggttgcagtg agctcagatc atgccactgc actccagcct gggcgacaga 3420 gcaagactcc gtcaaaaaaa aaaaaaaaaa aaagatttat gctggaaatc tggaaggacc 3480 caggaatatt agctcaaaga gccatcttaa gtccttttag aataaggcag ggtctgaatt 3540 gaaaagtgaa aataaaaaat tagctctggt ttaaaattga ttgttaggtg gaagaaacaa 3600 aaaatcaatt ataaaggcca catatttgta tgattctatt tatagagagt gctcagaata 3660 ggcaaatcta tagagacaga aagtagattg ttggttgcct agggagggag gcagggaagg 3720 tggtagggag ggaggaaatg gtagtgactg ctgatgggta tgggagtttt ttttagggtc 3780 atgaaaatgt tctaaaatat tgtacgactc tgtaaatata ctaaaaacca ttgaattgtt 3840 cactctaaat gtacaattgt acatgtgcaa atttgtacaa tttgtaaagt tatacaaaat 3900 aaatacaaat ttaaactgtg aattgctggt atgtgaatat ctcaataaag ctgttaatta 3960 attaattaat ttatttaaga cacagtctca ctctgtcgcc caggctggag tgcagtggcg 4020 caatctcagc tcattgcagc ctctgcctcc caggttcaag caattcttgt gactagcctc 4080 ccacatagct gggattacag gcgtgcacca ccacgccagg ctaattttta tatttttagt 4140 agagacgagg ttttgccatg ttggccaggc tggtcttgaa cttctggcct caaatgatca 4200 gcctgcctca gcttcccaaa atgctggggt tacaggtgtg agaaagctgt taaattaaaa 4260 aaaaatctta aaaattttaa agaattttat ttaaaaaaat ctatgatccc tcccacttga 4320 gaatgtctaa gtctaaatta ttcttaacct tcatcttgtg agatcttttc aatggcagaa 4380 agataatatt caccccaggc caggaagtac cattccattt tgcgggtgag aagagcaagg 4440 cctatacgta gaatgtaaca ggggcttttc gtcagctgta ctgaagaggc cagtggaact 4500 tcagatagga ggggatgaga agacaggaaa ggctggtgag ctgacattta taaagggagg 4560 agacttgacc ctgattctgg caattcaaag cagaaggaaa tggaagctaa tcccagctgt 4620 aacccagcta ctcgggagac tgaggcagga gaatcccctg aacccgggag gcggaggttg 4680 cagtgagctc agatcatgcc actgcactcc agcctgggcg acagagcaag actccgtcaa 4740 aataaataaa taaataatta aatatttaaa atgtttaaaa attttaattt aatacttttc 4800 tgtggcactt tggggctcaa ccaaagtgcc acagaaaagt agaagcagca gccttgggaa 4860 gattctgaag ggtaagtaga gaaggccttc aagattgagg aaacagcatg ggcacctggt 4920 ttgtgacagg aatggcttgt tagagaccag caggtggtat ggggaggctg gagtggggtg 4980 tgtggaggga tggagagcat ttgggccgga ctgtggacag cacaggatac tacagtcctt 5040 gctgatgact ttgagttcat tctgtggacc ctgaaggtct gggagaggat tttttttttt 5100 tgagacagtc tcactctgtc acccaggctg gaatgcaatg gcacgatctc ggctcactgc 5160 aacctctgct tcctgagttc aagcaattct cctgcctcag gctcctgaat agctaggatt 5220 acaggcatgt gccaccacgc ctggctaatt tttgtatttt tagtagagaa ggggtttcgc 5280 catgttgtcc aggctggtct caaactcctg acttcgtgat ctgcctgcct tagcctccca 5340 aagtgctggg attacaggcg tgagctaccg cgcccgactg aggatttttg ggtagtgatg 5400 gacagatctg catagggtct cacaagggat tttataaggt ggcagttctt gtatgaagtt 5460 actgagcctc ttaatggcca aactgacttc agtgcacagc caggggctca gttactttgg 5520 cagttgatct gacctgaacc atccatgcct gctttcttcc ctttcctttc tttctttttc 5580 tccttcctcc attcatcttc tccaattctt cctccatccc tttcccttgc ttccttcccc 5640 cttgtcccct ccctgagcct tgggtctgcc tggcatgttc ctgctgccca cactgatttg 5700 gttgtgctct gaggcagacc caggtagttc tgaattgtgc ttttcaatct tctagtggtc 5760 tgggcagtgt ggccccaaat gagcaggaag ggaggggtgc ccatcttctc taatgagtct 5820 ggacccaaga aggcaaggaa gaaagaaggc agaacaagga tagacttatg aaaaaggcat 5880 tatagcaacg agccacaggt tgctgtgggg cccagaaggg aagggttctt ttggggatgg 5940 gtctgtgtgc atggggagga gcatcctgtt tatttggttc aagctacttc acaaggacat 6000 gccctgttaa ttcacagtgc ttttcccgaa agcctactag aactaggcct ggtgagaggc 6060 cctgagaagg tgtatccttt tgtccaagag catctgggag aagaggcctg cctgacccaa 6120 gctgcagcaa agacacaagt ctgtaggtcc agatgtggac tctaccactg atttacaagt 6180 aggagttcct taacacttat ggaggacctc tgagaccgac acggtgcaag gccctggggt 6240 acaaagataa aaagccagag tcctccccat caaggcgcca cgggccctgt aaacacataa 6300 accgaggaca cactgcatga gagatcacca ataaacgatg tagccataca gtgcacaaac 6360 tgctcactca gtatgtgcta gaaaatagcc ccagaaggca aggctcaaga ggggaaatac 6420 agttaggaat gtggcaggct tctagcccgg gctctgccag tcctggctct gaactgcggt 6480 tttctcaacc ttgagatccc ttgtgtgctt ttagtatgct gaaggatcac tcacttcaga 6540 atgctagtga aaatacagat tcccaagtcc gaccccactg aatcacaatg gctggaggtc 6600 attcggggcc ccgaatctgc attttcaccc ccacccaccc cccgggcagc tttaatgttg 6660 gcaggctagg aaccacagtt cggattactg cttaacaggg agataataac ctgcttcaga 6720 cgagctaggt cagacgagca attcaagagc taacaaggca acatgcgcca aaagccttgt 6780 aaacctcagg gcagtacaat tctttgcaaa taatagtaat tcaatcatgc aaataataat 6840 aatagtaaac gaactggaga gcgcactgga aacgccgcat agtccagctg agtcggtgcc 6900 accgccccat ccactccagc gcagagggac tgtctcttta aggccccccc acctccccaa 6960 ccgcgtcgct tctcccttgg gtacctggcc cggccggcgg cgcgtgcgtg cagggcctcc 7020 cggcggggcg gtcgcggcgg cgcgacgccg gcgccgttgc gtgcgcgcct ggccctgccc 7080 ctttcccgcc ccttccccgc cccctcccct ccgcggggcc tcccccgccc gcgcggtaca 7140 gctgggtcag tgacgcgggc gctgcagccg tcgctaccgc cgcgttctat tctccgaagc 7200 cggcgaccgc cccacctcct ccctccctcc cgcccgcttc ctctgcccac agcgccggcc 7260 agagcgagct agacaagggc acgcggggcc tcgcctagac ccgagaagac tgcgggcgcg 7320 cgcaagcggc ggcgtggaag ctgtgagcgc ccccatcccg gaggtctccg ccggctcccg 7380 ggtgagttgt caccgcggcc cgggggcggc ggggccggca ttgtgccatc gacgcgctcg 7440 gccggctgtc aggggcgcgg gaccagcgcg caccgcccag gagtgacgct ggccggagcc 7500 cgggccggct tcggcggctc cccgcgcttc tctgcgccgg cccgctgtca cccggccgcg 7560 agccgcgccg ctgggagccc cgcgctggcg tggcgcggcc agccggccag cagtgggggt 7620 gcgcggccgg ggggaccggc ggctggtttg cggccgggaa cttggtgacc cgcggtccgg 7680 ggcgcgccgt cccgcgtcgc tgcccgggca gcaccggaag agccagacgc cgtgccgatg 7740 ggtgcagagg aggtaggcag aggccctctg tgccactgtc attactgccc tcagcccagc 7800 aaagctgcgg ggcttgcgct ggggcagggc tggcttagag aaggtggatt tcctgaggaa 7860 atctcagagc ccgcctgtgc gcaccgcggc attcgggagc ccccgcgcct cggctgctct 7920 ttaatctcaa aaacttctct tattaaccag gctaaactcc ccgaaaccag ctattttctt 7980 tcaaaaagta ggcacgtaca tacagacttt ccttttttcg cttggttttg agaccccagc 8040 tatgagtgtg gatctgactc tccctcatgg gagtcgtggc tggggagctg ctgaagtgga 8100 gaaaagttac cctggacgaa tttaggagca ggagggggag gtggttatgg ggacagcaag 8160 acccaggagc aaagaggcgt caaaataaag tcttgggctg gttaaaggga agttggcgtc 8220 tgggcaagga ggcctaaagc tgttgttccc acagaatttt ctttcagtgg caggcgacat 8280 gctgggcttt gttgctctcg ctaactgggc tcctgtgtgc tcttccagag gtgcagtaag 8340 attactcagt tcaattaggc ctagggattt actccctttt ttgatctaca gagatgggaa 8400 gtatgtcttt ccttcacagt agttaattca tttcttgctg ttttcgttcc tctggtgtaa 8460 aaacatacat aggagttacg cacacacacc ttttctgttt tgggaattcc acacccaaac 8520 tgtcaccatc tagtggaggc tagtagagac atgtgcttgg cactgacttc tgagttctct 8580 gggttttgtg tttttagcta gaagcatatt caaccagaaa ttaaaatttt cctggagttg 8640 ggggaggtat gtctacatct caggaaagaa ggtatttaag cagcaataat atggaaaggt 8700 tcttgaggac ttactgagta ccaacctttg tgctaagggc tttacttttt tgaactcatt 8760 taataacaga cttttgatgt agatattatt atccccattc ttctagttga gacccaaacc 8820 aaacaagtta aataactcgc ccatgtcaca taggtatctc atggtggagc ccacagtctg 8880 aactactaga ttatactgct agtttctggt ttgtttacct tttgataaaa ttgaacctgg 8940 agtctttcta aaaccttctg aaagcactgc tgcttcaggc tgtttctcag atcatgagca 9000 ttctaaactc tttctcctgg gtacacactt acggtatgtt tgcataagat tcatttgttc 9060 attctttcat tcagtactcc caagtagtta tgtgataccg aatgtatgcc aggcactgtg 9120 ctaggtattg caggtactgc attgaataag tcagaatcca gctctcatgg actcacagcc 9180 tttaagtcca tttgttttgg tttatgttgt tagctttcat tgctggccat ttgctgctga 9240 aggaacttct gcccagcgag ttaaacagag gacagtattg gtatgagtcc tgatagatag 9300 gacttcctgt ctgcagagta attttttgga tactgtagta gaaatggcat atgaaacaaa 9360 tcctcactta cacctagata gagacaggtg ccagggtgct cagtgtttaa accctgagag 9420 caaacccact gtcaaatggg caagtttgac ttctttcgct gaagcctgcc ttctgaaagc 9480 ccagaatttg gtgagataga agagaaagaa gggtagaatg aggtgttaca gatacaggct 9540 ggcagataaa gagacctcag cactttgtct gttttcctgg tcagtctctg aggtgtggtg 9600 attgaacttg tgttcttttt tattttttat tttttttgag atggagtctc gctctgtcac 9660 ccgggctgga gtgcagtggc acgatctcgg ctcactgcaa ccttcacctc ccaggttcaa 9720 acgattctct gcctcagcct cctgagcagc tgggactaca ggtgcgtgtc atcacgcctg 9780 gctaattttt gtatttttag tagagacttg gttttaccat gttggctagg ctggtctcga 9840 acgcctgacc tcaggtgatc tgcccgtctt ggcctcccaa agtgttggga ttacgggcgt 9900 gagccaccgt gcccggcctg aacttgtgtt cttatgtaat gttgcatctc tcagtagggg 9960 atgtcctcct ttgctctttt ggtggggcag caattcctgc agcagccttc cctctacatg 10020 cacacacaca ccccttccaa aaggtaataa ttcacctggt ttctttaaag ttagaacttc 10080 tttcaagttt attgctacta agcattgttt cactccctcc acacttgtcc atttcccaca 10140 taaaaacttg gcttttgctt caaatatttt cttctgccct tttttcatat ccttagctct 10200 tctgacaacc aagttactac tggtatcatt tgtaggctgg gagaaataca gcatctttaa 10260 aaaaaaatag tgaggtacat actcttcctc atttcagtac caaacaagtg aactgtggag 10320 aatgaagcag aaccacttgc cagcagagag ggaaggccag agggcacacg tggttgtctt 10380 tcccctctag ttccccattt attaagagac aattcacact tgcaggcccg aatgtcagca 10440 gatccattgg gcccaggttg tgtaattgcc atacatgaag tgagttatta agctcctgaa 10500 atgacatgct atctcctagt tgaagctgac aagcaggatt tattttccct cttctttctg 10560 tctggacact atggaagtct tgttagaggg tgttcgctca agcagtggga gaaagatcag 10620 aaggagccaa tagaggaggg agccccatgt cttgtcttct tttcaacttt gagagcaaac 10680 attgctttgt tgcagacttg aatgttgagg attaggacat ttggttaaat gtaag 10735 6 3761 DNA Homo sapiens 6 ccttgggtac ctggcccggc cggcggcgcg tgcgtgcagg gcctcccggc ggggcggtcg 60 cggcggcgcg acgccggcgc cgttgcgtgc gcgcctggcc ctgccccttt cccgcccctt 120 ccccgccccc tcccctccgc ggggcctccc ccgcccgcgc ggtacagctg ggtcagtgac 180 gcgggcgctg cagccgtcgc taccgccgcg ttctattctc cgaagccggc gaccgcccca 240 cctcctccct ccctcccgcc cgcttcctct gcccacagcg ccggccagag cgagctagac 300 aagggcacgc ggggcctcgc ctagacccga gaagactgcg ggcgcgcgca agcggcggcg 360 tggaagctgt gagcgccccc atcccggagg tctccgccgg ctcccgggtg agttgtcacc 420 gcggcccggg ggcggcgggg ccggcattgt gccatcgacg cgctcggccg gctgtcaggg 480 gcgcgggacc agcgcgcacc gcccaggagt gacgctggcc ggagcccggg ccggcttcgg 540 cggctccccg cgcttctctg cgccggcccg ctgtcacccg gccgcgagcc gcgccgctgg 600 gagccccgcg ctggcgtggc gcggccagcc ggccagcagt gggggtgcgc ggccgggggg 660 accggcggct ggtttgcggc cgggaacttg gtgacccgcg gtccggggcg cgccgtcccg 720 cgtcgctgcc cgggcagcac cggaagagcc agacgccgtg ccgatgggtg cagaggaggt 780 aggcagaggc cctctgtgcc actgtcatta ctgccctcag cccagcaaag ctgcggggct 840 tgcgctgggg cagggctggc ttagagaagg tggatttcct gaggaaatct cagagcccgc 900 ctgtgcgcac cgcggcattc gggagccccc gcgcctcggc tgctctttaa tctcaaaaac 960 ttctcttatt aaccaggcta aactccccga aaccagctat tttctttcaa aaagtaggca 1020 cgtacataca gactttcctt ttttcgcttg gttttgagac cccagctatg agtgtggatc 1080 tgactctccc tcatgggagt cgtggctggg gagctgctga agtggagaaa agttaccctg 1140 gacgaattta ggagcaggag ggggaggtgg ttatggggac agcaagaccc aggagcaaag 1200 aggcgtcaaa ataaagtctt gggctggtta aagggaagtt ggcgtctggg caaggaggcc 1260 taaagctgtt gttcccacag aattttcttt cagtggcagg cgacatgctg ggctttgttg 1320 ctctcgctaa ctgggctcct gtgtgctctt ccagaggtgc agtaagatta ctcagttcaa 1380 ttaggcctag ggatttactc ccttttttga tctacagaga tgggaagtat gtctttcctt 1440 cacagtagtt aattcatttc ttgctgtttt cgttcctctg gtgtaaaaac atacatagga 1500 gttacgcaca cacacctttt ctgttttggg aattccacac ccaaactgtc accatctagt 1560 ggaggctagt agagacatgt gcttggcact gacttctgag ttctctgggt tttgtgtttt 1620 tagctagaag catattcaac cagaaattaa aattttcctg gagttggggg aggtatgtct 1680 acatctcagg aaagaaggta tttaagcagc aataatatgg aaaggttctt gaggacttac 1740 tgagtaccaa cctttgtgct aagggcttta cttttttgaa ctcatttaat aacagacttt 1800 tgatgtagat attattatcc ccattcttct agttgagacc caaaccaaac aagttaaata 1860 actcgcccat gtcacatagg tatctcatgg tggagcccac agtctgaact actagattat 1920 actgctagtt tctggtttgt ttaccttttg ataaaattga acctggagtc tttctaaaac 1980 cttctgaaag cactgctgct tcaggctgtt tctcagatca tgagcattct aaactctttc 2040 tcctgggtac acacttacgg tatgtttgca taagattcat ttgttcattc tttcattcag 2100 tactcccaag tagttatgtg ataccgaatg tatgccaggc actgtgctag gtattgcagg 2160 tactgcattg aataagtcag aatccagctc tcatggactc acagccttta agtccatttg 2220 ttttggttta tgttgttagc tttcattgct ggccatttgc tgctgaagga acttctgccc 2280 agcgagttaa acagaggaca gtattggtat gagtcctgat agataggact tcctgtctgc 2340 agagtaattt tttggatact gtagtagaaa tggcatatga aacaaatcct cacttacacc 2400 tagatagaga caggtgccag ggtgctcagt gtttaaaccc tgagagcaaa cccactgtca 2460 aatgggcaag tttgacttct ttcgctgaag cctgccttct gaaagcccag aatttggtga 2520 gatagaagag aaagaagggt agaatgaggt gttacagata caggctggca gataaagaga 2580 cctcagcact ttgtctgttt tcctggtcag tctctgaggt gtggtgattg aacttgtgtt 2640 cttttttatt ttttattttt tttgagatgg agtctcgctc tgtcacccgg gctggagtgc 2700 agtggcacga tctcggctca ctgcaacctt cacctcccag gttcaaacga ttctctgcct 2760 cagcctcctg agcagctggg actacaggtg cgtgtcatca cgcctggcta atttttgtat 2820 ttttagtaga gacttggttt taccatgttg gctaggctgg tctcgaacgc ctgacctcag 2880 gtgatctgcc cgtcttggcc tcccaaagtg ttgggattac gggcgtgagc caccgtgccc 2940 ggcctgaact tgtgttctta tgtaatgttg catctctcag taggggatgt cctcctttgc 3000 tcttttggtg gggcagcaat tcctgcagca gccttccctc tacatgcaca cacacacccc 3060 ttccaaaagg taataattca cctggtttct ttaaagttag aacttctttc aagtttattg 3120 ctactaagca ttgtttcact ccctccacac ttgtccattt cccacataaa aacttggctt 3180 ttgcttcaaa tattttcttc tgcccttttt tcatatcctt agctcttctg acaaccaagt 3240 tactactggt atcatttgta ggctgggaga aatacagcat ctttaaaaaa aaatagtgag 3300 gtacatactc ttcctcattt cagtaccaaa caagtgaact gtggagaatg aagcagaacc 3360 acttgccagc agagagggaa ggccagaggg cacacgtggt tgtctttccc ctctagttcc 3420 ccatttatta agagacaatt cacacttgca ggcccgaatg tcagcagatc cattgggccc 3480 aggttgtgta attgccatac atgaagtgag ttattaagct cctgaaatga catgctatct 3540 cctagttgaa gctgacaagc aggatttatt ttccctcttc tttctgtctg gacactatgg 3600 aagtcttgtt agagggtgtt cgctcaagca gtgggagaaa gatcagaagg agccaataga 3660 ggagggagcc ccatgtcttg tcttcttttc aactttgaga gcaaacattg ctttgttgca 3720 gacttgaatg ttgaggatta ggacatttgg ttaaatgtaa g 3761 7 909 DNA Mus musculus 7 atgtgccatg gcaggatagc accaaagagc agctcagagt ttgttgtgac ttctgtgggg 60 catggagtgt ttcttcaact ggtgatcctt tgcgctctgc tgggagatgg attagcctct 120 gtgtgtcctc tgcccccaga gccagagaat ggtggctaca tttgccaccc ccggccttgt 180 aaagacccct tgacaacagg cagtgtcatc gagtacctgt gtgcagaagg ctacatgttg 240 aagggtgact acaaatacct gacctgcaaa aatggcgagt ggacgccagc catggaggtt 300 agctgtcatc tcattgaaga caaagaaacc catgcacttg gggtccctgc gctgtccata 360 gtggcttcca ctgccagctc tgtggcactc attctcctcc tcgtggtgct gtttgtactg 420 ctgcagccaa agctgaagtc tttccatcat agcaggcgtg aacagggggt ttctggggat 480 caagtctcca ttatggtgga tggtgtccag gttgcactac cttcacatga ggaagctgtg 540 tatggaagtt ctggtcactg catgccacca gctgatccca gagtacagat tgttctgtcg 600 gaagggtctg cacctagtgg gaggaacatg ccaagggaac agcagctgca aggtcaggag 660 gcctgctctt ctgcaggtgg agaggacgag gccccgggcc attctgggct gtgtgaagcc 720 tggggttccc agggctcaga gactgtgatg gtgcatcagg caaccacatc ttcctgggtg 780 gccggctcag ggagcagccg gccgacacac aaagacactg cagattcaga aaacagtgac 840 atacaaagcc ttttatccct gacatcacag gagtacacag atgatatccc actgttgaaa 900 gaagcatga 909 8 302 PRT Mus musculus 8 Met Cys His Gly Arg Ile Ala Pro Lys Ser Ser Ser Glu Phe Val Val 1 5 10 15 Thr Ser Val Gly His Gly Val Phe Leu Gln Leu Val Ile Leu Cys Ala 20 25 30 Leu Leu Gly Asp Gly Leu Ala Ser Val Cys Pro Leu Pro Pro Glu Pro 35 40 45 Glu Asn Gly Gly Tyr Ile Cys His Pro Arg Pro Cys Lys Asp Pro Leu 50 55 60 Thr Thr Gly Ser Val Ile Glu Tyr Leu Cys Ala Glu Gly Tyr Met Leu 65 70 75 80 Lys Gly Asp Tyr Lys Tyr Leu Thr Cys Lys Asn Gly Glu Trp Thr Pro 85 90 95 Ala Met Glu Val Ser Cys His Leu Ile Glu Asp Lys Glu Thr His Ala 100 105 110 Leu Gly Val Pro Ala Leu Ser Ile Val Ala Ser Thr Ala Ser Ser Val 115 120 125 Ala Leu Ile Leu Leu Leu Val Val Leu Phe Val Leu Leu Gln Pro Lys 130 135 140 Leu Lys Ser Phe His His Ser Arg Arg Glu Gln Gly Val Ser Gly Asp 145 150 155 160 Gln Val Ser Ile Met Val Asp Gly Val Gln Val Ala Leu Pro Ser His 165 170 175 Glu Glu Ala Val Tyr Gly Ser Ser Gly His Cys Met Pro Pro Ala Asp 180 185 190 Pro Arg Val Gln Ile Val Leu Ser Glu Gly Ser Ala Pro Ser Gly Arg 195 200 205 Asn Met Pro Arg Glu Gln Gln Leu Gln Gly Gln Glu Ala Cys Ser Ser 210 215 220 Ala Gly Gly Glu Asp Glu Ala Pro Gly His Ser Gly Leu Cys Glu Ala 225 230 235 240 Trp Gly Ser Gln Gly Ser Glu Thr Val Met Val His Gln Ala Thr Thr 245 250 255 Ser Ser Trp Val Ala Gly Ser Gly Ser Ser Arg Pro Thr His Lys Asp 260 265 270 Thr Ala Asp Ser Glu Asn Ser Asp Ile Gln Ser Leu Leu Ser Leu Thr 275 280 285 Ser Gln Glu Tyr Thr Asp Asp Ile Pro Leu Leu Lys Glu Ala 290 295 300 9 2464 DNA Homo sapiens 9 tcgaggaatt taggagcagg agggggaggt ggttatgggg acagcaagac ccaggagcaa 60 agaggcgtca aaataaagtc ttgggctggt taaagggaag ttggcgtctg ggcaaggagg 120 cctaaagctg ttgttcccac agaattttct ttcagtggca ggcgacatgc tgggctttgt 180 tgctctcgct aactgggctc ctgtgtgctc ttccagaggt gcagtaagat tactcagttc 240 aattaggcct agggatttac tccctttttt gatctacaga gatgggaagt atgtctttcc 300 ttcacagtag ttaattcatt tcttgctgtt ttcgttcctc tggtgtaaaa acatacatag 360 gagttacgca cacacacctt ttctgttttg ggaattccac acccaaactg tcaccatcta 420 gtggaggcta gtagagacat gtgcttggca ctgacttctg agttctctgg gttttgtgtt 480 tttagctaga agcatattca accagaaatt aaaattttcc tggagttggg ggaggtatgt 540 ctacatctca ggaaagaagg tatttaagca gcaataatat ggaaaggttc ttgaggactt 600 actgagtacc aacctttgtg ctaagggctt tacttttttg aactcattta ataacagact 660 tttgatgtag atattattat ccccattctt ctagttgaga cccaaaccaa acaagttaaa 720 taactcgccc atgtcacata ggtatctcat ggtggagccc acagtctgaa ctactagatt 780 atactgctag tttctggttt gtttaccttt tgataaaatt gaacctggag tctttctaaa 840 accttctgaa agcactgctg cttcaggctg tttctcagat catgagcatt ctaaactctt 900 tctcctgggt acacacttac ggtatgtttg cataagattc atttgttcat tctttcattc 960 agtactccca agtagttatg tgataccgaa tgtatgccag gcactgtgct aggtattgca 1020 ggtactgcat tgaataagtc agaatccagc tctcatggac tcacagcctt taagtccatt 1080 tgttttggtt tatgttgtta gctttcattg ctggccattt gctgctgaag gaacttctgc 1140 ccagcgagtt aaacagagga cagtattggt atgagtcctg atagatagga cttcctgtct 1200 gcagagtaat tttttggata ctgtagtaga aatggcatat gaaacaaatc ctcacttaca 1260 cctagataga gacaggtgcc agggtgctca gtgtttaaac cctgagagca aacccactgt 1320 caaatgggca agtttgactt ctttcgctga agcctgcctt ctgaaagccc agaatttggt 1380 gagatagaag agaaagaagg gtagaatgag gtgttacaga tacaggctgg cagataaaga 1440 gacctcagca ctttgtctgt tttcctggtc agtctctgag gtgtggtgat tgaacttgtg 1500 ttctttttta ttttttattt tttttgagat ggagtctcgc tctgtcaccc gggctggagt 1560 gcagtggcac gatctcggct cactgcaacc ttcacctccc aggttcaaac gattctctgc 1620 ctcagcctcc tgagcagctg ggactacagg tgcgtgtcat cacgcctggc taatttttgt 1680 atttttagta gagacttggt tttaccatgt tggctaggct ggtctcgaac gcctgacctc 1740 aggtgatctg cccgtcttgg cctcccaaag tgttgggatt acgggcgtga gccaccgtgc 1800 ccggcctgaa cttgtgttct tatgtaatgt tgcatctctc agtaggggat gtcctccttt 1860 gctcttttgg tggggcagca attcctgcag cagccttccc tctacatgca cacacacacc 1920 ccttccaaaa ggtaataatt cacctggttt ctttaaagtt agaacttctt tcaagtttat 1980 tgctactaag cattgtttca ctccctccac acttgtccat ttcccacata aaaacttggc 2040 ttttgcttca aatattttct tctgcccttt tttcatatcc ttagctcttc tgacaaccaa 2100 gttactactg gtatcatttg taggctggga gaaatacagc atctttaaaa aaaaatagtg 2160 aggtacatac tcttcctcat ttcagtacca aacaagtgaa ctgtggagaa tgaagcagaa 2220 ccacttgcca gcagagaggg aaggccagag ggcacacgtg gttgtctttc ccctctagtt 2280 ccccatttat taagagacaa ttcacacttg caggcccgaa tgtcagcaga tccattgggc 2340 ccaggttgtg taattgccat acatgaagtg agttattaag ctcctgaaat gacatgctat 2400 ctcctagttg aagctgacaa gcaggattta ttttccctct tctttctgtc tggacactat 2460 ggaa 2464 10 914 DNA Homo sapiens 10 gggctggagt gcagtggcac gatctcggct cactgcaacc ttcacctccc aggttcaaac 60 gattctctgc ctcagcctcc tgagcagctg ggactacagg tgcgtgtcat cacgcctggc 120 taatttttgt atttttagta gagacttggt tttaccatgt tggctaggct ggtctcgaac 180 gcctgacctc aggtgatctg cccgtcttgg cctcccaaag tgttgggatt acgggcgtga 240 gccaccgtgc ccggcctgaa cttgtgttct tatgtaatgt tgcatctctc agtaggggat 300 gtcctccttt gctcttttgg tggggcagca attcctgcag cagccttccc tctacatgca 360 cacacacacc ccttccaaaa ggtaataatt cacctggttt ctttaaagtt agaacttctt 420 tcaagtttat tgctactaag cattgtttca ctccctccac acttgtccat ttcccacata 480 aaaacttggc ttttgcttca aatattttct tctgcccttt tttcatatcc ttagctcttc 540 tgacaaccaa gttactactg gtatcatttg taggctggga gaaatacagc atctttaaaa 600 aaaaatagtg aggtacatac tcttcctcat ttcagtacca aacaagtgaa ctgtggagaa 660 tgaagcagaa ccacttgcca gcagagaggg aaggccagag ggcacacgtg gttgtctttc 720 ccctctagtt ccccatttat taagagacaa ttcacacttg caggcccgaa tgtcagcaga 780 tccattgggc ccaggttgtg taattgccat acatgaagtg agttattaag ctcctgaaat 840 gacatgctat ctcctagttg aagctgacaa gcaggattta ttttccctct tctttctgtc 900 tggacactat ggaa 914 11 1203 DNA Homo sapiens 11 tcgaggaatt taggagcagg agggggaggt ggttatgggg acagcaagac ccaggagcaa 60 agaggcgtca aaataaagtc ttgggctggt taaagggaag ttggcgtctg ggcaaggagg 120 cctaaagctg ttgttcccac agaattttct ttcagtggca ggcgacatgc tgggctttgt 180 tgctctcgct aactgggctc ctgtgtgctc ttccagaggt gcagtaagat tactcagttc 240 aattaggcct agggatttac tccctttttt gatctacaga gatgggaagt atgtctttcc 300 ttcacagtag ttaattcatt tcttgctgtt ttcgttcctc tggtgtaaaa acatacatag 360 gagttacgca cacacacctt ttctgttttg ggaattccac acccaaactg tcaccatcta 420 gtggaggcta gtagagacat gtgcttggca ctgacttctg agttctctgg gttttgtgtt 480 tttagctaga agcatattca accagaaatt aaaattttcc tggagttggg ggaggtatgt 540 ctacatctca ggaaagaagg tatttaagca gcaataatat ggaaaggttc ttgaggactt 600 actgagtacc aacctttgtg ctaagggctt tacttttttg aactcattta ataacagact 660 tttgatgtag atattattat ccccattctt ctagttgaga cccaaaccaa acaagttaaa 720 taactcgccc atgtcacata ggtatctcat ggtggagccc acagtctgaa ctactagatt 780 atactgctag tttctggttt gtttaccttt tgataaaatt gaacctggag tctttctaaa 840 accttctgaa agcactgctg cttcaggctg tttctcagat catgagcatt ctaaactctt 900 tctcctgggt acacacttac ggtatgtttg cataagattc atttgttcat tctttcattc 960 agtactccca agtagttatg tgataccgaa tgtatgccag gcactgtgct aggtattgca 1020 ggtactgcat tgaataagtc agaatccagc tctcatggac tcacagcctt taagtccatt 1080 tgttttggtt tatgttgtta gctttcattg ctggccattt gctgctgaag gaacttctgc 1140 ccagcgagtt aaacagagga cagtattggt atgagtcctg atagatagga cttcctgtct 1200 gca 1203 12 575 DNA Homo sapiens 12 gcagccttcc ctctacatgc acacacacac cccttccaaa aggtaataat tcacctggtt 60 tctttaaagt tagaacttct ttcaagttta ttgctactaa gcattgtttc actccctcca 120 cacttgtcca tttcccacat aaaaacttgg cttttgcttc aaatattttc ttctgccctt 180 ttttcatatc cttagctctt ctgacaacca agttactact ggtatcattt gtaggctggg 240 agaaatacag catctttaaa aaaaaatagt gaggtacata ctcttcctca tttcagtacc 300 aaacaagtga actgtggaga atgaagcaga accacttgcc agcagagagg gaaggccaga 360 gggcacacgt ggttgtcttt cccctctagt tccccattta ttaagagaca attcacactt 420 gcaggcccga atgtcagcag atccattggg cccaggttgt gtaattgcca tacatgaagt 480 gagttattaa gctcctgaaa tgacatgcta tctcctagtt gaagctgaca agcaggattt 540 attttccctc ttctttctgt ctggacacta tggaa 575 13 1203 DNA Homo sapiens 13 tcgaggaatt taggagcagg agggggaggt ggttatgggg acagcaagac ccaggagcaa 60 agaggcgtca aaataaagtc ttgggctggt taaagggaag ttggcgtctg ggcaaggagg 120 cctaaagctg ttgttcccac agaattttct ttcagtggca ggcgacatgc tgggctttgt 180 tgctctcgct aactgggctc ctgtgtgctc ttccagaggt gcagtaagat tactcagttc 240 aattaggcct agggatttac tccctttttt gatctacaga gatgggaagt atgtctttcc 300 ttcacagtag ttaattcatt tcttgctgtt ttcgttcctc tggtgtaaaa acatacatag 360 gagttacgca cacacacctt ttctgttttg ggaattccac acccaaactg tcaccatcta 420 gtggaggcta gtagagacat gtgcttggca ctgacttctg agttctctgg gttttgtgtt 480 tttagctaga agcatattca accagaaatt aaaattttcc tggagttggg ggaggtatgt 540 ctacatctca ggaaagaagg tatttaagca gcaataatat ggaaaggttc ttgaggactt 600 actgagtacc aacctttgtg ctaagggctt tacttttttg aactcattta ataacagact 660 tttgatgtag atattattat ccccattctt ctagttgaga cccaaaccaa acaagttaaa 720 taactcgccc atgtcacata ggtatctcat ggtggagccc acagtctgaa ctactagatt 780 atactgctag tttctggttt gtttaccttt tgataaaatt gaacctggag tctttctaaa 840 accttctgaa agcactgctg cttcaggctg tttctcagat catgagcatt ctaaactctt 900 tctcctgggt acacacttac ggtatgtttg cataagattc atttgttcat tctttcattc 960 agtactccca agtagttatg tgataccgaa tgtatgccag gcactgtgct aggtattgca 1020 ggtactgcat tgaataagtc agaatccagc tctcatggac tcacagcctt taagtccatt 1080 tgttttggtt tatgttgtta gctttcattg ctggccattt gctgctgaag gaacttctgc 1140 ccagcgagtt aaacagagga cagtattggt atgagtcctg atagatagga cttcctgtct 1200 gca 1203 14 1637 DNA Homo sapiens 14 tcgaggaatt taggagcagg agggggaggt ggttatgggg acagcaagac ccaggagcaa 60 agaggcgtca aaataaagtc ttgggctggt taaagggaag ttggcgtctg ggcaaggagg 120 cctaaagctg ttgttcccac agaattttct ttcagtggca ggcgacatgc tgggctttgt 180 tgctctcgct aactgggctc ctgtgtgctc ttccagaggt gcagtaagat tactcagttc 240 aattaggcct agggatttac tccctttttt gatctacaga gatgggaagt atgtctttcc 300 ttcacagtag ttaattcatt tcttgctgtt ttcgttcctc tggtgtaaaa acatacatag 360 gagttacgca cacacacctt ttctgttttg ggaattccac acccaaactg tcaccatcta 420 gtggaggcta gtagagacat gtgcttggca ctgacttctg agttctctgg gttttgtgtt 480 tttagctaga agcatattca accagaaatt aaaattttcc tggagttggg ggaggtatgt 540 ctacatctca ggaaagaagg tatttaagca gcaataatat ggaaaggttc ttgaggactt 600 actgagtacc aacctttgtg ctaagggctt tacttttttg aactcattta ataacagact 660 tttgatgtag atattattat ccccattctt ctagttgaga cccaaaccaa acaagttaaa 720 taactcgccc atgtcacata ggtatctcat ggtggagccc acagtctgaa ctactagatt 780 atactgctag tttctggttt gtttaccttt tgataaaatt gaacctggag tctttctaaa 840 accttctgaa agcactgctg cttcaggctg tttctcagat catgagcatt ctaaactctt 900 tctcctgggt acacacttac ggtatgtttg cataagattc atttgttcat tctttcattc 960 agtactccca agtagttatg tgataccgaa tgtatgccag gcactgtgct aggtattgca 1020 ggtactgcat tgaataagtc agaatccagc tctcatggac tcacagcctt taagtccatt 1080 tgttttggtt tatgttgtta gctttcattg ctggccattt gctgctgaag gaacttctgc 1140 ccagcgagtt aaacagagga cagtattggt atgagtcctg atagatagga cttcctgtct 1200 gcagagtaat tttttggata ctgtagtaga aatggcatat gaaacaaatc ctcacttaca 1260 cctagataga gacaggtgcc agggtgctca gtgtttaaac cctgagagca aacccactgt 1320 caaatgggca agtttgactt ctttcgctga agcctgcctt ctgaaagccc agaatttggt 1380 gagatagaag agaaagaagg gtagaatgag gtgttacaga tacaggctgg cagataaaga 1440 gacctcagca ctttgtctgt tttcctggtc agtctctgag gtgtggtgat tgaacttgtg 1500 ttctttttta ttttttattt tttttgagat ggagtctcgc tctgtcaccc gggctggagt 1560 gcagtggcac gatctcggct cactgcaacc ttcacctccc aggttcaaac gattctctgc 1620 ctcagcctcc tgagcag 1637 15 577 DNA Homo sapiens 15 cagcagcctt ccctctacat gcacacacac accccttcca aaaggtaata attcacctgg 60 tttctttaaa gttagaactt ctttcaagtt tattgctact aagcattgtt tcactccctc 120 cacacttgtc catttcccac ataaaaactt ggcttttgct tcaaatattt tcttctgccc 180 ttttttcata tccttagctc ttctgacaac caagttacta ctggtatcat ttgtaggctg 240 ggagaaatac agcatcttta aaaaaaaata gtgaggtaca tactcttcct catttcagta 300 ccaaacaagt gaactgtgga gaatgaagca gaaccacttg ccagcagaga gggaaggcca 360 gagggcacac gtggttgtct ttcccctcta gttccccatt tattaagaga caattcacac 420 ttgcaggccc gaatgtcagc agatccattg ggcccaggtt gtgtaattgc catacatgaa 480 gtgagttatt aagctcctga aatgacatgc tatctcctag ttgaagctga caagcaggat 540 ttattttccc tcttctttct gtctggacac tatggaa 577 16 956 DNA Homo sapiens 16 ggtacctggc ccggccggcg gcgcgtgcgt gcagggcctc ccggcggggc ggtcgcggcg 60 gcgcgacgcc ggcgccgttg cgtgcgcgcc tggccctgcc cctttcccgc cccttccccg 120 ccccctcccc tccgcggggc ctcccccgcc cgcgcggtac agctgggtca gtgacgcggg 180 cgctgcagcc gtcgctaccg ccgcgttcta ttctccgaag ccggcgaccg ccccacctcc 240 tccctccctc ccgcccgctt cctctgccca cagcgccggc cagagcgagc tagacaaggg 300 cacgcggggc ctcgcctaga cccgagaaga ctgcgggcgc gcgcaagcgg cggcgtggaa 360 gctgtgagcg cccccatccc ggaggtctcc gccggctccc gggtgagttg tcaccgcggc 420 ccgggggcgg cggggccggc attgtgccat cgacgcgctc ggccggctgt caggggcgcg 480 ggaccagcgc gcaccgccca ggagtgacgc tggccggagc ccgggccggc ttcggcggct 540 ccccgcgctt ctctgcgccg gcccgctgtc acccggccgc gagccgcgcc gctgggagcc 600 ccgcgctggc gtggcgcggc cagccggcca gcagtggggg ctgcgcggcc ggggggaccg 660 gcggctggtt tgcggccggg aacttggtga cccgcggtcc ggggcgcgcc gtcccgcgtc 720 gctgcccggg cagcaccgga agagccagac gccgtgccga tgggtgcaga ggaggtaggc 780 agaggccctc tgtgccactg tcattactgc cctcagccca gcaaagctgc ggggcttgcg 840 ctggggcagg gctggcttag agaaggtgga tttcctgagg aaatctcaga gcccgcctgt 900 gcgcaccgcg gcattcggga gcccccgcgc ctcggctgct ctttaatctc aaaaac 956 17 26 DNA Unknown human or mouse 17 ctcgagtgcc atggcaggat agcacc 26 18 26 DNA Unknown human or mouse 18 tctagatcat gcttctttca acagtg 26 19 25 DNA Homo sapiens 19 ctcgagtgca tggcaggata gcacc 25 

1. An isolated oncosuppressive polypeptide having the amino acid sequence of SEQ ID N. 2 or
 8. 2. An isolated DNA molecule encoding the polypeptide of claim 1, which is selected from SEQ ID N. 1, 2 and
 4. 3. An isolated DNA molecule regulating the expression of the polypeptide of claim 1, which is selected from the group consisting of SEQ ID N. 3, 5, 6, 9, 10, 11, 12, 13, 14, 15,
 16. 4. An isolated DNA molecule according to claim 3, having transcription promoter activity responsive to p53 and p73, which is selected from the group consisting of SEQ ID N. 9, 10, 11, 12, 13, 14,
 15. 5. An isolated nucleic acid molecule or analog thereof able to hybridize with the DNA molecules of claim 2, or with a complementary strand thereof.
 6. A genetic construct wherein a sequence selected from SEQ ID N: 3, 5, 6 and 9-15 is functionally linked to a reporter gene.
 7. A method for the screening of compounds able to modulate the activity of a DNA molecule according to claim 3, which comprises incubating cells transfected with a construct of wherein a sequence selected from SEQ ID N: 3, 5, 6 and 9-15 is functionally linked to a reporter gene in the presence of a candidate compound, and subsequently determining the reporter-gene expression.
 8. The use of a nucleic acid according to claim 2, of a nucleic acid molecule or analog thereof able to hybridize thereto for the preparation of an antitumor medicament.
 9. The use of a polypeptide according to claim 1, for the preparation of an antitumor medicament. 